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Elevated plasma N-terminal (NT)-proBNP levels and coronary calcium score (CCS) not only predicts myocardial ischaemia and coronary artery stenosis but also adverse cardiovascular events and mortality in type 2 diabetic patients with an increased urinary albumin excretion rate (UAER), whereas low levels are associated with low frequency of coronary artery disease (CAD) and good prognosis. The underlying causes of poor prognosis in patients with elevated NT-proBNP are not known; thus, we investigated the role of putative asymptomatic CAD in type 2 diabetic patients with UAER30 mg/24 h and elevated P-NT-proBNP and/or CCS.We identified 200 type 2 diabetic patients without known CAD and with normal creatinine levels. Patients with P-NT-proBNP45.2 ng/L (the median P-NT-proBNP value in this cohort and in accordance with our previous findings) and/or CCS ≥ 400 were stratified as high-risk patients for CAD (n = 133) and all other patients as low-risk patients (n = 67). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109) and/or computer tomography angiography (n = 20) and/or coronary angiography (CAG; n = 86).All patients received intensive mulitifactorial intervention. In 70 of 133 (53%) high-risk patients, significant CAD was demonstrated by MPI and/or CAG, corresponding to 35% (70/200) of the total cohort. Among high-risk patients, CCS but not P-NT-proBNP was paralleled by increased prevalence of significant CAD and in the 86 patients where CAG was performed, a CCS100 had a negative predictive value for coronary artery stenosis of 94% (P = 0.04).Our study revealed that50% of asymptomatic type 2 diabetic patients with UAER30 mg/24 h had significant CAD based on risk stratification with P-NT-proBNP and CCS. This provides some explanation to the previously reported poor prognosis in these asymptomatic patients. Optimized cardio protective treatment in these patients is warranted.

ObjectiveNon-obese patients with type 2 diabetes (T2DM) are characterized by predominant defective insulin secretion. However, in non-obese T2DM patients, metformin, targeting insulin resistance, is non-inferior to the prandial insulin secretagogue, repaglinide, controlling overall glycaemia (HbA1c). Whether the same apply for postprandial glucose and lipid metabolism is unknown. Here, we compared the effect of metformin versus repaglinide on postprandial metabolism in non-obese T2DM patients.DesignSingle-centre, double-masked, double-dummy, crossover study during 2×4 months involving 96 non-obese (body mass index≤27 kg/m2) insulin-naïve T2DM patients. At enrolment, patients stopped prior oral hypoglycaemic agents therapies and after a 1-month run-in period on diet-only treatment, patients were randomized to repaglinide (2 mg) thrice daily followed by metformin (1 g) twice daily or vice versa each during 4 months with 1-month washout between interventions.MethodsPostprandial metabolism was evaluated by a standard test meal (3515 kJ; 54% fat, 13% protein and 33% carbohydrate) with blood sampling 0–6 h postprandially.ResultsFasting levels and total area under the curve (AUC) for plasma glucose, triglycerides and free fatty acids (FFA) changed equally between treatments. In contrast, fasting levels and AUC of total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and serum insulin were lower during metformin than repaglinide (mean (95% confidence intervals), LDL cholesterol difference metformin versus repaglinide: AUC: −0.17 mmol/l (−0.26; −0.08)). AUC differences remained significant after adjusting for fasting levels.ConclusionsIn non-obese T2DM patients, metformin reduced postprandial levels of glycaemia, triglycerides and FFA similarly compared to the prandial insulin secretagogue, repaglinide. Furthermore, metformin reduced fasting and postprandial cholesterolaemia and insulinaemia compared with repaglinide. These data support prescription of metformin as the preferred drug in non-obese patients with T2DM targeting fasting and postprandial glucose and lipid metabolism.

BACKGROUND: Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems. METHODS: Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n=2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent-offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing. RESULTS: In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions. CONCLUSIONS: The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients.

Objective: Derangements of the GH–IGF-I axis have been associated with microalbuminuria (MA) in type 1 diabetes. The aim of this study was to investigate whether anIGF-Igene promoter polymorphism influenced the development of persistent MA in type 1 diabetes.Design: A prospective follow-up study of a cohort of 277 patients with newly diagnosed type 1 diabetes consecutively enrolled between September 1979 and August 1984.Methods: Urinary albumin excretion rate over 24 h was measured in each patient at least once a year. Persistent MA was defined as a urinary albumin excretion rate between 30 and 300 mg/24 h.Results: During a median follow-up of 18.0 years (range 1.0–21.5), 79 of 277 patients developed persistent MA.IGF-Igene genotype was available for 216 subjects; in 73% of the subjects, the wild-type genotype of this IGF-I gene polymorphism was present, while 27% had the variant type. At baseline, there were no differences in IGF-I levels and HbA1cvalues between subjects with the wild type and subjects with variant type. By Kaplan–Meier analysis, subjects with the variant type of this polymorphism had during follow-up a higher risk of development of MA compared subjects with the wild type (P= 0.03).Conclusions: Subjects with the variant type of anIGF-Igene polymorphism had a significantly increased risk of developing MA. This risk was not mediated through changes in circulating IGF-I levels. Our study suggests that in type 1 diabetes, thisIGF-Igene polymorphism is a risk factor of MA.

Objective: The bone-related peptide osteoprotegerin (OPG) has recently been found in increased amounts in the vasculature in diabetes. It is produced by vascular smooth muscle and endothelial cells, and may be implicated in the development of vascular calcifications. OPG is present in the circulation, where increased amounts have been observed in patients with diabetes. In this study, we examined whether plasma OPG is associated with the glycaemic and vascular status of patients with type 1 diabetes. Methods: Two gender-, age- and duration-comparable groups of type 1 diabetic patients either with (n = 199) or without (n = 192) signs of diabetic nephropathy were studied. Plasma OPG was determined by an ELISA. Results: The plasma OPG concentration was significantly higher in patients with nephropathy than those without (3.11 (2.49–3.99) vs 2.57 (2.19–3.21) (median (interquartiles), ng/ml), P < 0.001). Plasma OPG correlated with haemoglobin A1c (HbA1c), systolic blood pressure and age in both groups and, in addition, with kidney function in the nephropathic group. These correlations remained significant in multivariate models. In addition, we found that plasma OPG concentrations were increased among patients with cardiovascular diseases (CVD), both in the normoalbuminuric and the nephropathic groups. The differences between nephropathic and normoalbuminuric, as well as subgroups with and without CVD, could largely be ascribed to changes in HbA1c, age, systolic blood pressure and creatinine. Conclusion: OPG is associated with glycaemic control and CVD in patients with type 1 diabetes, compatible with the hypothesis that OPG is associated with the development of diabetic vascular complications.

Background. Intervention studies in microalbuminuric type 2 diabetic patients have demonstrated that it is possible to avoid progression to overt diabetic nephropathy and even to achieve regression to normoalbuminuria. However, the long-term impact of stabilization/ regression in albuminuria on decline in glomerular filtration rate (GFR) has not been established. Methods. 151 patients with type 2 diabetes and microalbuminuria at baseline in whom GFR was measured at least three times during 7.8 years of follow-up were divided into three groups according to the level of albuminuria during follow-up. Overt nephropathy was diagnosed as a urinary albumin excretion rate (AER) >300 mg/24 h and remission to normoalbuminuria was defined as an AER

BACKGROUND Blockade of the renin-angiotensin system is the primary target in the treatment of diabetic kidney disease. Angiotensin II subtype 1 (AT1) receptor antagonists reduce albuminuria and lower blood pressure, but the initial time course of these effects after initiation of treatment is unknown. We evaluated the time course of the antihypertensive and antialbuminuric effect after initiation of AT1 receptor blockade by losartan in diabetic nephropathy. METHODS Ten hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, patients received losartan 100 mg once daily for 28 days. Every morning, one urine sample was collected for daily determination of albumin/creatinine ratio. Twenty-four hour blood pressure (Takeda TM2420), plasma renin and plasma creatinine were measured at baseline and days 7, 14 and 28. RESULTS Baseline levels of urinary albumin/creatinine ratio and 24 h mean arterial blood pressure were 676 (402-1136) mg/g (geometric mean and 95% CI, respectively) and 100+/-3 mmHg (mean +/- SEM). Albumin/creatinine ratio was significantly reduced after 7 days of treatment by 29% (15-41) (95% CI) without significant further reductions during the 28 day study period (P

Background. An XbaI polymorphism in the gene encoding the glucose transporter, GLUT-1, is associated with development of diabetic nephropathy in Chinese type 2 diabetic patients. In addition, an amino acid variant (K121Q) in the gene encoding the glycoprotein plasma cell differentiating antigen (PC-1), a specific inhibitor of insulin receptor signalling, has been reported to predict a faster progression of nephropathy in Italian and British type 1 diabetic patients. Methods. The XbaI and K121Q polymorphisms were determined by PCR-RFLP in Danish type 1 diabetic patients with nephropathy (122 men 77 women, age 40.9 ± 9.6 years, diabetes duration 27 ± 8 years) and type I diabetic patients with persistent normoalbuminuria (118 men/74 women, age 42.7 ± 10.2 years, diabetes duration 26 ± 9 years). Proliferative retinopathy was present in 156 patients (40%), while 67 patients (17%) had no diabetic retinopathy. Results. There were no differences in the frequency of GLUT-1 XbaI genotypes between type I diabetic patients with diabetic nephropathy and type 1 diabetic patients with normoalbuminuria: 72 (41%)/87 (50%) 16 (9%) vs 94 (49%)/74 (39%)/24 (13%) had GLUT-1 XbaI +/+, +/- or -/- genotype respectively (NS). The frequency of PC-I KK, KQ and QQ genotypes were 141 (71%)/52 (26%)/6 (3%) vs 138 (73%)/45 (24%)/7 (4%) in patients respectively with and without nephropathy (NS). Neither were associations between the investigated polymorphisms and simplex or proliferative retinopathy revealed. Conclusions. Neither the PC-1 K121Q nor the GLUT-1 XbaI polymorphism contribute to the genetic susceptibility of diabetic microvascular complications in Danish type 1 diabetic patients.

disease, diabetic complications, diabetic nephropathy, PAI-1 polymorphism, type 1 diabetes Background. A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of Introduction diabetic micro- and macrovascular complications. Methods. We studied 198 type 1 diabetic patients with Several studies of familial clustering in diabetic nephrodiabetic nephropathy [121 men, age (mean±SD) pathy have suggested a genetic component in the 41±10 years, diabetes duration 28±8 years] and 192 pathogenesis of this devastating microvascular compatients with persistent normoalbuminuria (118 men, plication [1–3]. The increased cardiovascular mortality age 43±10 years, diabetes duration 27±9 years). and morbidity observed, not only in diabetic patients Results. Male patients with nephropathy had elev- with kidney disease [4], but also in their non-diabetic ated plasma PAI-1 levels [geometric mean (95% CI )], parents [5], have led investigators to assume a possible 70 (62–79) ng/ml, compared with normoalbumin- analogous process leading to atherosclerosis and glomuric men, 43 (38–47) ng/ml, P

Identification of studies Diabetic nephropathy is a leading cause of end-stage renal failure in the Western world, and the number of Studies with a case–control and/or cross-sectional diabetic patients needing dialysis or kidney transdesign were considered, without language limitations, plantation is increasing steadily [1]. While the possibilprovided that they were published as original articles. ities for treatment of these patients have improved All studies were included which contained sufficient substantially by introduction of antihypertensive information to allow a comparison of ACE/ID therapy and, perhaps particularly, angiotensingenotype distributions between adult cases (with converting enzyme (ACE) inhibitors, our knowledge IDDM/NIDDM and elevated urinary albumin excreof the mechanisms involved in the development of this tion rate, as defined by the authors) and diabetic devastating microvascular complication is still sparse. controls without an elevated urinary albumin excretion Studies of familial clustering [2–4] and genetic prerate. Where studies on the same cases and control disposition [5,6 ] suggest that genetic factors are subjects had been reported more than once, only one involved in the pathogenesis of diabetic nephropathy. study was included. Abstracts were excluded and One candidate gene is the gene coding for ACE in unpublished studies were not sought. which an insertion/deletion polymorphism (ACE/ID) Studies were identified by an electronic search has been described [7]. Based on the presence [insertion performed on Current